Development of the kidney begins when the ureteric bud invades the metanephric mesenchyme and induces it to change to an epithelial phenotype. The induced mesenchyme then induces the ureteric bud to branch. The major aim of our Program is to identify new molecules that are critical in this process. The four independent members of this PPG have already identified new genes critical to nephrogenesis. Dr Costantini discovered that deletion of the c-ret oncogene or its ligand GDNF causes renal agenesis. He is now identifying the down stream signals by which ret induces ureteric bud branching. He recently generated mice which express GFP in the ureteric bud that were used by Dr Mendelsohn to map the three-dimensional trajectory of the ureteric bud as it travels towards the bladder. She identified a wedge of mesenchyme destined to form the bladder trigone and found that retinoids are critical for its differentiation. Mendelsohn also identified a new reciprocal induction loop whereby metanephric stromal cells signal the ureteric bud to induce expression of ret and is now proposing to examine the role of retinoids in the formation of the lower urinary tract. It is well known that retinoid deficiency in pregnant women (and other mammals) results in the birth of children with lower urinary tract anomalies. Dr Barasch identified the long sought molecule that the ureteric bud secretes to induce the conversion of metanephric mesenchyme to epithelia. He recently discovered a second inducing factor, lipocalin that is an iron transport protein thereby identifying a completely new iron transport pathway in cells. This pathway is critical for kidney development and targets a separate stage in nephrogenesis. Dr A1-Awqati discovered that the metanephric mesenchyme contains stem cells capable of generating all the epithelial cells of the nephron. He also demonstrated the existence of pluripotent stem cells located in the papilla, which are likely to be involved in the repair of the kidney during injury. These four scientists with complementary expertise will collaborate by using genetic, biochemical and cellular methods to examine the structure and function of these new genes and their role in the formation of the three dimensional architecture of the kidney. While it is obvious that congenital renal dysplasias must be caused by mutations in these and other morphogenetic genes, there is evidence that genetically determined differences in the number of functioning nephrons might be central to the development of hypertension and other kidney diseases. Hence, studies of the early stages of kidney development, the stage at which the number ofnephrons is determined are likely to have wide clinical implications.